CD147 and Corneal Wound Repair

描述（由申请人提供）：角膜损伤后的愈合过程是通过释放大量蛋白质启动的，这些蛋白质分解上皮连接并有助于上皮层移动以覆盖受伤区域。基质金属蛋白酶（MMP）是降解细胞表面和细胞外基质组分的蛋白水解酶家族，在这一过程中起着关键作用。在未受伤的角膜中几乎检测不到，它们的诱导被认为在伤口愈合和慢性伤口的建立中起关键作用。MMPs的产生和活化受到复杂机制的严格调控，包括CD 147的同源寡聚化，CD 147是一种在肿瘤细胞中高度表达的高度N-糖基化的跨膜蛋白。我们最近发现，CD 147是半乳糖凝集素-3的一种新的细胞表面反受体，半乳糖凝集素-3是一种已知聚集的半乳糖苷结合凝集素。 细胞表面受体更重要的是，我们发现半乳糖凝集素-3对CD 147的聚集显著上调MMP 9，MMP 9是由角膜上皮细胞迁移以重新覆盖伤口合成和分泌的主要金属蛋白酶。该提案的长期目标是确定半乳糖凝集素-3诱导CD 147聚集是否是与角膜伤口修复相关的生理和病理重塑过程的有力调节机制。以下具体目标将实现这一目标：（1）研究通过半乳糖凝集素-3的CD 147聚集作为角膜上皮细胞中的集体细胞脱离和细胞迁移的调节剂的作用，并确定通过MMP 9的半乳糖凝集素-3的降解是否抑制CD 147聚集，从而构成负反馈机制以防止持续的角膜重塑，（2）研究CD 147 N-糖基化在调节半乳糖凝集素-3结合亲和力、CD 147聚集和MMP 9诱导中的作用，和（3）表征CD 147/半乳糖凝集素-3复合物在创伤愈合和复发性糜烂的小鼠模型中的生物学作用，并确定抑制半乳糖凝集素-3受体聚集和CD 147功能在复发性上皮创伤愈合期间是否具有治疗潜力。这项研究将首次探索将聚糖动力学与受伤组织启动上皮细胞脱离和迁移的生物过程联系起来的分子机制，并将更好地了解慢性伤口的发病机制。

DESCRIPTION (provided by applicant): The healing process after corneal injury is initiated through the release of a number of proteins that disassemble the epithelial junctions and contribute to the movement of the epithelial sheet to cover the wounded area. Matrix metalloproteinases (MMPs), a family of proteolytic enzymes that degrade components of the cell surface and extracellular matrix, are central to this process. Barely detected in unwounded cornea, their induction is thought to play a key role during wound healing and in the establishment of chronic wounds. The production and activation of MMPs are tightly regulated by complex mechanisms that include homo-oligomerization of CD147, a heavily N-glycosylated transmembrane protein highly expressed in tumor cells. We recently discovered that CD147 is a novel cell surface counter-receptor for galectin-3, a �alactoside-binding lectin known to cluster cell surface receptors. More importantly, we found that clustering of CD147 by galectin-3 dramatically upregulates MMP9, the primary metalloproteinase synthesized and secreted by corneal epithelial cells migrating to resurface a wound. The long-term objective of this proposal is to determine whether induction of CD147 clustering by galectin-3 is a powerful regulatory mechanism of the physiological and pathological remodeling processes associated with wound repair in the cornea. The following specific aims will address this objective: (1) to investigate te role of CD147 clustering by galectin-3 as modulator of collective cell detachment and cell migration in corneal epithelial cells, and to determine whether degradation of the galectin-3 by MMP9 inhibits CD147 clustering, thereby constituting a negative feedback mechanism to prevent sustained corneal remodeling, (2) to investigate the role of CD147 N-glycosylation in modulating galectin-3 binding affinity, CD147 clustering, and MMP9 induction, and (3) to characterize the biological role of the CD147/galectin-3 complex in mouse models of wound healing and recurrent erosion, and determine whether inhibiting galectin-3 receptor clustering and CD147 function have a therapeutic potential during recurrent epithelial wound healing. This research will explore, for the first time, the molecular mechanism linking glycan dynamics to the biological process by which wounded tissue initiates epithelial cell detachment and migration, and will provide better insight into the pathogenesis of chronic wounds.